Apolipoprotein M promoter polymorphisms alter promoter activity and confer the susceptibility to the development of type 1 diabetes.
ABSTRACT Apolipoprotein M plays an important role in the formation of prebeta-HDL and cholesterol efflux to HDL. In the present study, we investigate the potential association between the ApoM promoter polymorphisms and type 1 diabetes.
The study was conducted in Peking Union Medical College, Beijing, China and Karolinska Institutet, Stockholm, Sweden. Two populations, including 493 Han Chinese subjects (177 T1D patients/316 controls) and 225 Swedish (124/101), are enrolled in the present study. Three single nucleotide polymorphisms (SNP) C-1065A, T-855C and T-778C in the promoter region of the ApoM gene are genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Promoter activity was measured by reporter gene assay.
SNP T-778C was strongly associated with T1D in both Han Chinese (p=0.002, OR=2.188, CI 95%=1.338-3.581) and Swedish (p=0.021, OR=2.865, CI 95%=1.128-7.278) populations. The luciferase activity of -778C promoter was 1.41 times as high as that of -778T promoter (9.90+/-1.92 vs. 7.04+/-0.76, p=0.001).
Allele C of SNP T-778C may increase promoter activity and confer the risk susceptibility to the development of T1D.
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ABSTRACT: High-density lipoprotein (HDL) has been proposed to enhance β-cell functions. Clinical studies have suggested that apolipoprotein M (apoM), which rides mainly on HDL, is involved in diabetes; however, the underlying mechanism has not yet been elucidated. Recently, apoM was shown to be a carrier for sphingosine 1-phosphate (S1P), a bioactive lipid mediator. In the present study, we investigated the modulation of insulin secretion by apoM through the action of S1P. We overexpressed apoM in the livers of C57BL6 mice using adenovirus gene transfer and found that the blood glucose levels under ad libitum feeding conditions were lower in the apoM-overexpressing mice. While an insulin tolerance test revealed that insulin sensitivity was not significantly affected, a glucose tolerance test revealed that apoM-overexpressing mice had a better glucose tolerance because of enhanced insulin secretion, a phenomenon that was reversed by treatment with VPC 23019, an antagonist against S1P1 and S1P3 receptor. In vitro experiments with MIN6 cells also revealed that apoM-containing lipoproteins enhanced insulin secretion, which was again inhibited by VPC 23019. ApoM retarded the degradation of S1P, and an increase in Pdx1 expression, the attenuation of endoreticulum stress, and the phosphorylation of Akt, AmpK, and Erk were observed as possible underlying mechanisms for the effect of S1P, maintained at a high concentration by apoM, on the increase in insulin secretion. ApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions.Biochimica et Biophysica Acta 05/2014; · 4.66 Impact Factor
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ABSTRACT: Backgrounds: It has been reported that rs940494 and rs805296 SNPs of apolipoprotein M (apoM) gene may confer the risk in the development of type 2 diabetes (T2D) and coronary artery disease (CAD) in the Han Chinese. However, a recent study demonstrated that rs805297 polymorphism is significantly associated with reduced total high density lipoprotein (HDL) levels in rheumatoid arthritis patients. But the relationship between rs805297 SNP and CAD has not been explored. The aim of the present study was to elucidate whether the rs805297 mutant allele is implicated in CAD and links to changes in blood lipid levels in these patients. Three hundred CAD patients and three hundred and twelve non-CAD patients were subjected in the present study. All subjects were confirmed by the angiography. Plasma concentrations of apoM were semi-quantitatively determined by dot-blotting analysis, and total serum lipid levels were quantified using an automated RA-1000 (Technician, USA). The genotyping of rs805297 of apoM was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotype and allele frequencies were not significant (P=0.5798 and 0.3834, respectively) between cases and controls. Compared with the wild-type C/C genotype, carriers of the C/A and A/A genotypes did not have an increased risk of CAD, as determined by multiple logistic regression analysis, after adjustment for age, sex, BMI, history of smoking, hypertension and hypercholesterolemia. (CA, odds ratio = 0.49, 95% confidence interval 0.15-1.87, P = 0.462; AA, odds ratio = 0.51, 95% confidence interval 0.13-1.68, P = 0.534). The plasma concentration levels of apoM did not differ significantly among carriers of the three genotypes between two groups. Lastly, control subjects with A/A genotypes had lower total levels of HDL cholesterol than did those with C/C genotypes. The results presented here suggest that the rs805297 SNP is not associated with an increased risk of developing CAD, although it does independently correlate with dyslipidaemia in Han Chinese individuals.Lipids in Health and Disease 12/2013; 12(1):184. · 2.31 Impact Factor
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ABSTRACT: The present study investigated the correlation among genetic polymorphisms of the proximal promoter region of apolipoprotein M (apoM) gene, the polymorphisms in relation to apoM expressions and the susceptibility to coronary artery diseases (CAD) in a Han Chinese population. Four common polymorphic sites, i.e., T-1628G, C-1065A, T-855C and T-778C, were confirmed, and a new deletion mutation C-724del was found, in 206 CAD patients and 209 non-CAD patients using direct DNA sequencing analyses. Occurrences of alleles T-1628G, T-855C and C-724del were significantly higher in CAD patients compared to non-CAD patients. Moreover we examined all these polymorphisms in relation to apoM expression by applying luciferase reporter assay. It demonstrated that constructs -855C and 724del showed obvious decreased luciferase activities, i.e., (0.93±0.15 vs. 2.11±0.15; P=0.012) and (1.13±0.25 vs. 2.11±0.15; P=0.009) respectively, which indicates these two polymorphisms could confer decreased apoM expressions. Meanwhile the occurrences of these two SNP were also significantly higher in the CAD patients than in non-CAD patients. It is therefore reasonable to speculate that down-regulated apoM expressions in relation to these polymorphisms may affect HDL and cholesterol metabolism in vivo and further influence the susceptibility to CAD, although the underlying mechanisms need further investigation.International journal of medical sciences 01/2014; 11(4):365-72. · 2.07 Impact Factor